Yoshitsugu Iwakura

Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling in primary aldosteronism.

Adrenal vein sampling (AVS) is fundamental for subtype diagnosis in patients with primary aldosteronism. AVS protocols vary between centers, especially for diagnostic indices and for use of adrenocorticotropic hormone (ACTH) stimulation. We investigated the role of both continuous ACTH infusion and bolus on the performance and interpretation of AVS in a sample of 76 patients with confirmed primary aldosteronism. In 36 primary aldosteronism patients, AVS was performed both under basal conditions and after continuous ACTH infusion, and in 40 primary aldosteronism patients, AVS was performed both under basal conditions and after ACTH IV bolus. Both ACTH protocols determined an increase in the rate of successful cannulation of the adrenal veins. Both ACTH infusion and bolus determined a significant increase in selectivity index for the right adrenal vein and ACTH bolus for the left adrenal vein. Lateralization index was not significantly different after continuous ACTH infusion and IV bolus. In 88% and 78% of the patients, the diagnosis obtained was the same before and after ACTH infusion and IV bolus, respectively. However, the reproducibility of the diagnosis was reduced using less stringent criteria for successful cannulation of the adrenal veins. This study shows that ACTH use during AVS may be of help for centers with lower success rates, because a successful adrenal cannulation is more easily obtained with this protocol; moreover, this technique performs at least as well as the unstimulated strategy and in some cases may be even better. Stringent criteria for cannulation should be used to have a high consistency of the diagnosis.

Predictors of decreasing glomerular filtration rate and prevalence of chronic kidney disease after treatment of primary aldosteronism: renal outcome of 213 cases.

CONTEXT In primary aldosteronism (PA), glomerular hyperfiltration due to excessive aldosterone is considered to underestimate actual renal damage. OBJECTIVE Our objectives were to determine the prevalence of chronic kidney disease (CKD) in PA and identify the predictors of decreasing estimated glomerular filtration rate (eGFR) after treatment. DESIGN AND SETTING This was a 12-month prospective study of patients with PA treated at Tohoku University Hospital. PATIENTS AND INTERVENTIONS All patients were treated according to the results of adrenal venous sampling; 102 patients with aldosterone-producing adenoma underwent adrenalectomy, and 111 with bilateral hyperaldosteronism were treated with mineralocorticoid receptor antagonists. MAIN OUTCOME MEASURES Electrolytes, blood pressure, and indicators of renal function were determined at 1 and 12 months after intervention. RESULTS Blood pressure, urinary albumin excretion (UAE), and eGFR, which significantly decreased at 1 month after treatment of PA, did not further decrease at 12 months. Prevalence of CKD, which was 15.7% in aldosterone-producing adenoma and 8.1% in bilateral hyperaldosteronism at the first visit, increased to 37.1% and 28.3%, respectively, at the end of study (P < .0001). Multivariate regression analysis revealed that higher UAE and lower serum potassium levels were found to be independent predictors of decreasing eGFR after intervention. CONCLUSIONS This large cohort study shows that the prevalence of CKD in PA was increased after treatment and that higher UAE and lower serum potassium levels at the first visit were predictors of decreasing eGFR after treatment of PA. To prevent a large decrease of eGFR after intervention, PA patients should be diagnosed before evolution to severe albuminuria and hypokalemia.

Aldosterone Suppression on Contralateral Adrenal During Adrenal Vein Sampling Does Not Predict Blood Pressure Response After Adrenalectomy

CONTEXT Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers. OBJECTIVE The objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA. SETTING The study was carried out in eight different referral centers in Italy, Germany, and Japan. PATIENTS From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses. RESULTS Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy. CONCLUSIONS For patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.

Different Expression of 11β-Hydroxylase and Aldosterone Synthase Between Aldosterone-Producing Microadenomas and Macroadenomas

Aldosterone-producing adenoma is a major subtype of primary aldosteronism. The number of cases of these adenomas, which are below the detection limit of computed tomography but diagnosed by adrenal venous sampling, has recently been increasing. However, the pathophysiology of these adenomas, especially those manifesting clinically overt hyperaldosteronism despite their small size, remains unknown. Therefore, we examined the correlation between tumor size and the status of intratumoral steroidogenic enzymes involved in aldosterone biosynthesis using immunohistochemistry. Forty patients with surgically proven aldosterone-producing adenomas were retrospectively studied. Multidetector computed tomography, adrenal venous sampling, and laparoscopic adrenalectomy were performed in all of the patients studied. The tumor area at the maximum diameter of the sections was precisely measured by ImageJ software. The status of the steroidogenic enzymes was immunohistochemically analyzed, and the findings were evaluated according to the H-score system, based on both the number of immunopositive cells and relative immunointensity. Adrenal masses were not detected by computed tomography in 20 patients. Blood pressure, plasma aldosterone concentration, urinary aldosterone excretion, and the number of antihypertensive agents also decreased significantly after the surgery in these patients, as well as in the patients with adenomas detectable by computed tomography. Maximum tumor area obtained in the specimens was significantly correlated with preoperative plasma aldosterone concentration, urinary aldosterone excretion, and the H score of 11&bgr;-hydroxylase and was inversely correlated with the H score of aldosterone synthase. These results demonstrated that small adenomas could produce sufficient aldosterone to cause clinically overt primary aldosteronism because of the significantly higher aldosterone synthase expression per tumor area.

Measurement of Peripheral Plasma 18-Oxocortisol Can Discriminate Unilateral Adenoma From Bilateral Diseases in Patients With Primary Aldosteronism

Adrenal venous sampling is currently the only reliable method to distinguish unilateral from bilateral diseases in primary aldosteronism. In this study, we attempted to determine whether peripheral plasma levels of 18-oxocortisol (18oxoF) and 18-hydroxycortisol could contribute to the clinical differentiation between aldosteronoma and bilateral hyperaldosteronism in 234 patients with primary aldosteronism, including computed tomography (CT)–detectable aldosteronoma (n=113) and bilateral hyperaldosteronism (n=121), all of whom underwent CT and adrenal venous sampling. All aldosteronomas were surgically resected and the accuracy of diagnosis was clinically and histopathologically confirmed. 18oxoF and 18-hydroxycortisol were measured using liquid chromatography tandem mass spectrometry. Receiver operating characteristic analysis of 18oxoF discrimination of adenoma from hyperplasia demonstrated sensitivity/specificity of 0.83/0.99 at a cut-off value of 4.7 ng/dL, compared with that based on 18-hydroxycortisol (sensitivity/specificity: 0.62/0.96). 18oxoF levels above 6.1 ng/dL or of aldosterone >32.7 ng/dL were found in 95 of 113 patients with aldosteronoma (84%) but in none of 121 bilateral hyperaldosteronism, 30 of whom harbored CT-detectable unilateral nonfunctioning nodules in their adrenals. In addition, 18oxoF levels below 1.2 ng/dL, the lowest in aldosteronoma, were found 52 of the 121 (43%) patients with bilateral hyperaldosteronism. Further analysis of 27 patients with CT-undetectable micro aldosteronomas revealed that 8 of these 27 patients had CT-detectable contralateral adrenal nodules, the highest values of 18oxoF and aldosterone were 4.8 and 24.5 ng/dL, respectively, both below their cut-off levels indicated above. The peripheral plasma 18oxoF concentrations served not only to differentiate aldosteronoma but also could serve to avoid unnecessary surgery for nonfunctioning adrenocortical nodules concurrent with hyperplasia or microadenoma.

Is there a role for segmental adrenal venous sampling and adrenal sparing surgery in patients with primary aldosteronism

OBJECTIVE AND DESIGN Adrenal venous sampling (AVS) is critical to determine the subtype of primary aldosteronism (PA). Central AVS (C-AVS)--that is, the collection of effluents from bilateral adrenal central veins (CV)--sometimes does not allow differentiation between bilateral aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism. To establish the best treatment course, we have developed segmental AVS (S-AVS); that is, we collect effluents from the tributaries of CV to determine the intra-adrenal sources of aldosterone overproduction. We then evaluated the clinical utility of this novel approach in the diagnosis and treatment of PA. METHODS We performed C-AVS and/or S-AVS in 297 PA patients and assessed the accuracy of diagnosis based on the results of C-AVS (n=138, 46.5%) and S-AVS (n=159, 53.5%) by comparison with those of clinicopathological evaluation of resected specimens. RESULTS S-AVS demonstrated both elevated and attenuated secretion of aldosterone from APA and non-tumorous segments, respectively, in patients with bilateral APA and recurrent APA. These findings were completely confirmed by detailed histopathological examination after surgery. S-AVS, but not C-AVS, also served to identify APA located distal from the CV. CONCLUSIONS Compared to C-AVS, S-AVS served to identify APA in some patients, and its use should expand the pool of patients eligible for adrenal sparing surgery through the identification of unaffected segments, despite the fact that S-AVS requires more expertise and time. Especially, this new technique could enormously benefit patients with bilateral or recurrent APA because of the preservation of non-tumorous glandular tissue.

Measurement of Peripheral Plasma 18-Oxocortisol Can Discriminate Unilateral Adenoma From Bilateral Diseases in Patients With Primary AldosteronismNovelty and Significance

Adrenal venous sampling is currently the only reliable method to distinguish unilateral from bilateral diseases in primary aldosteronism. In this study, we attempted to determine whether peripheral plasma levels of 18-oxocortisol (18oxoF) and 18-hydroxycortisol could contribute to the clinical differentiation between aldosteronoma and bilateral hyperaldosteronism in 234 patients with primary aldosteronism, including computed tomography (CT)–detectable aldosteronoma (n=113) and bilateral hyperaldosteronism (n=121), all of whom underwent CT and adrenal venous sampling. All aldosteronomas were surgically resected and the accuracy of diagnosis was clinically and histopathologically confirmed. 18oxoF and 18-hydroxycortisol were measured using liquid chromatography tandem mass spectrometry. Receiver operating characteristic analysis of 18oxoF discrimination of adenoma from hyperplasia demonstrated sensitivity/specificity of 0.83/0.99 at a cut-off value of 4.7 ng/dL, compared with that based on 18-hydroxycortisol (sensitivity/specificity: 0.62/0.96). 18oxoF levels above 6.1 ng/dL or of aldosterone >32.7 ng/dL were found in 95 of 113 patients with aldosteronoma (84%) but in none of 121 bilateral hyperaldosteronism, 30 of whom harbored CT-detectable unilateral nonfunctioning nodules in their adrenals. In addition, 18oxoF levels below 1.2 ng/dL, the lowest in aldosteronoma, were found 52 of the 121 (43%) patients with bilateral hyperaldosteronism. Further analysis of 27 patients with CT-undetectable micro aldosteronomas revealed that 8 of these 27 patients had CT-detectable contralateral adrenal nodules, the highest values of 18oxoF and aldosterone were 4.8 and 24.5 ng/dL, respectively, both below their cut-off levels indicated above. The peripheral plasma 18oxoF concentrations served not only to differentiate aldosteronoma but also could serve to avoid unnecessary surgery for nonfunctioning adrenocortical nodules concurrent with hyperplasia or microadenoma.

Intra-adrenal Aldosterone Secretion: Segmental Adrenal Venous Sampling for Localization

PURPOSE To use segmental adrenal venous sampling (AVS) (S-AVS) of effluent tributaries (a version of AVS that, in addition to helping identify aldosterone hypersecretion, also enables the evaluation of intra-adrenal hormone distribution) to detect and localize intra-adrenal aldosterone secretion. MATERIALS AND METHODS The institutional review board approved this study, and all patients provided informed consent. S-AVS was performed in 65 patients with primary aldosteronism (34 men; mean age, 50.9 years ± 11 [standard deviation]). A microcatheter was inserted in first-degree tributary veins. Unilateral aldosterone hypersecretion at the adrenal central vein was determined according to the lateralization index after cosyntropin stimulation. Excess aldosterone secretion at the adrenal tributary vein was considered to be present when the aldosterone/cortisol ratio from this vein exceeded that from the external iliac vein; suppressed secretion was indicated by the opposite pattern. Categoric variables were expressed as numbers and percentages; continuous variables were expressed as means ± standard errors of the mean. RESULTS The AVS success rate, indicated by a selectivity index of 5 or greater, was 98% (64 of 65). The mean numbers of sampled tributaries on the left and right sides were 2.11 and 1.02, respectively. The following diagnoses were made on the basis of S-AVS results: unilateral aldosterone hypersecretion in 30 patients, bilateral hypersecretion without suppressed segments in 22 patients, and bilateral hypersecretion with at least one suppressed segment in 12 patients. None of the patients experienced severe complications. CONCLUSION S-AVS could be used to identify heterogeneous intra-adrenal aldosterone secretion. Patients who have bilateral aldosterone-producing adenomas can be treated with adrenal-sparing surgery or other minimally invasive local therapies if any suppressed segment is identified at S-AVS.

A case of bilateral aldosterone-producing adenomas differentiated by segmental adrenal venous sampling for bilateral adrenal sparing surgery

Primary aldosteronism due to unilateral aldosterone-producing adenoma (APA) is a surgically curable form of hypertension. Bilateral APA can also be surgically curable in theory but few successful cases can be found in the literature. It has been reported that even using successful adrenal venous sampling (AVS) via bilateral adrenal central veins, it is extremely difficult to differentiate bilateral APA from bilateral idiopathic hyperaldosteronism (IHA) harbouring computed tomography (CT)-detectable bilateral adrenocortical nodules. We report a case of bilateral APA diagnosed by segmental AVS (S-AVS) and blood sampling via intra-adrenal first-degree tributary veins to localize the sites of intra-adrenal hormone production. A 36-year-old man with marked long-standing hypertension was referred to us with a clinical diagnosis of bilateral APA. He had typical clinical and laboratory profiles of marked hypertension, hypokalaemia, elevated plasma aldosterone concentration (PAC) of 45.1 ng dl−1 and aldosterone renin activity ratio of 90.2 (ng dl−1 per ng ml−1 h−1), which was still high after 50 mg-captopril loading. CT revealed bilateral adrenocortical tumours of 10 and 12 mm in diameter on the right and left sides, respectively. S-AVS confirmed excess aldosterone secretion from a tumour segment vein and suppressed secretion from a non-tumour segment vein bilaterally, leading to the diagnosis of bilateral APA. The patient underwent simultaneous bilateral sparing adrenalectomy. Histopathological analysis of the resected adrenals together with decreased blood pressure and PAC of 5.2 ng dl−1 confirmed the removal of bilateral APA. S-AVS was reliable to differentiate bilateral APA from IHA by direct evaluation of intra-adrenal hormone production.

Renal Resistive Index Predicts Postoperative Blood Pressure Outcome in Primary Aldosteronism

The renal resistive index (RI) calculated by Doppler ultrasonography has been reported to be correlated with renal structural changes and outcomes in patients with essential hypertension or renal disease. However, little is known about this index in primary aldosteronism. In this prospective study, we examined the utility of this index to predict blood pressure (BP) outcome after adrenalectomy in patients with primary aldosteronism. We studied 94 patients with histopathologically proven aldosteronoma who underwent surgery. Parameters on renal function, including renal flow indices, were examined and followed up for 12 months postoperatively. The renal RI of the main, hilum, and interlobar arteries was significantly higher in patients with aldosteronoma compared with 100 control patients. BP, estimated glomerular filtration rate, and urinary albumin excretion significantly decreased after adrenalectomy. The resistive indices of all compartment arteries were significantly reduced 1 month after adrenalectomy and remained stable for 12 months. Patients whose interlobar RI was in the highest tertile at baseline had higher systolic BP after adrenalectomy than those whose RI was in the lowest tertile. Logistic regression analysis demonstrated that the RI of the interlobar and hilum arteries could be an independent predictive marker for intractable hypertension (systolic BP ≥140 mm Hg, increased BP, taking ≥3 antihypertensive agents, or increased number of agents) even after adrenalectomy. Therefore, in patients with aldosteronoma, the renal RI indicates partially reversible renal hemodynamics and renal structural damages that would influence postoperative BP outcome.